WO2024192004A1 - Protéines de détection du cancer de l'ovaire et leurs procédés d'utilisation - Google Patents

Protéines de détection du cancer de l'ovaire et leurs procédés d'utilisation Download PDF

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WO2024192004A1
WO2024192004A1 PCT/US2024/019543 US2024019543W WO2024192004A1 WO 2024192004 A1 WO2024192004 A1 WO 2024192004A1 US 2024019543 W US2024019543 W US 2024019543W WO 2024192004 A1 WO2024192004 A1 WO 2024192004A1
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proteins
subject
ovarian cancer
concentration
treatment
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Ashkan AFSHIN
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Novelna Inc
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Novelna Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57545—Immunoassay; Biospecific binding assay; Materials therefor for cancer of the ovaries
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the five- year survival rate is 47%, but it is 89% if the cancer is diagnosed when the cancer is at stage I, 71% when diagnosed at stage II, 41% when diagnosed at stage III, and only 20% when diagnosed at stage IV (Torre et al., 2018).
  • stromal tumors which account for about 5% of ovarian tumors, are associated with a five-year survival rate of 98% if the cancer is diagnosed at stage I, but 41% if diagnosed at stage IV (id.).
  • Another aspect of the invention relates to a method of detecting ovarian cancer in a subject, the method comprising determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; and applying a classifier to the concentration of the one or more proteins that identifies whether the concentration of the one or more proteins is indicative that ovarian cancer is detected.
  • Yet another aspect of the invention relates to a method of treating ovarian cancer in a subject, comprising acquiring results from a method of detecting ovarian cancer in a subject as described herein, and administering a treatment to the subject.
  • Another aspect of the invention relates to a method of evaluating a treatment for ovarian cancer in a subject, the method comprising administering a treatment for ovarian cancer, and determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1.
  • Another aspect of the invention relates to a method of evaluating the efficacy of a treatment for ovarian cancer in a subject, the method comprising administering a treatment for ovarian cancer to the subject, and determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1.
  • the method further comprises administering an adjusted treatment when it is determined that the treatment requires adjustment.
  • Another aspect of the invention relates to a method of treating ovarian cancer in a subject, the method comprising administering a treatment for ovarian cancer to the subject, and determining in a biological sample from the subject a concentration of one or more proteins to evaluate whether cancer is recurring, wherein the one or more proteins are selected from Table 1.
  • the method further comprises administering a second treatment when it is determined that the cancer is recurring.
  • the biological sample is selected from a plasma sample, serum sample, saliva sample, cerebrospinal fluid (CSF)sample, sweat sample, urine sample, or tear sample.
  • CSF cerebrospinal fluid
  • the biological sample is a urine sample.
  • the one or more proteins are selected from Table 2.
  • the one or more proteins are selected from Table 3.
  • the one or more proteins are selected from Table 4.
  • the one or more proteins are each protein from Table 4.
  • Another aspect of the invention relates to a method of measuring amounts of proteins in a subject, the method comprising determining individual amounts of one or more proteins selected from Table 1.
  • Yet another aspect of the invention relates to a method of measuring amounts of proteins in a subject, the method comprising determining individual amounts of one or more proteins selected from Table 2.
  • Another aspect of the invention relates to a method of measuring amounts of proteins in a subject, the method comprising determining individual amounts of one or more proteins selected from Table 3.
  • Attorney Docket No. NVLNA.003.WO1 Another aspect of the invention relates to a method of measuring amounts of proteins in a subject, the method comprising determining individual amounts of one or more proteins selected from Table 4. In certain embodiments, the method comprises determining individual amounts of each protein from Table 4.
  • Another aspect of the invention relates to a kit comprising one or more components that can be used to perform assays for detecting one or more proteins of Table 1, or one or more proteins of Table 2, or one or more proteins of Table 3, or one or more proteins of Table 4.
  • the one or more proteins are selected from Table 2. In certain embodiments, the one or more proteins are selected from Table 3. In some embodiments, the one or more proteins are selected from Table 4. In certain embodiments, the one or more proteins are each protein from Table 4. BRIEF DESCRIPTION OF THE FIGURES [0030] FIG.1 shows accuracy, measured as area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, of detecting ovarian cancer in a subject using random combinations of two to 20 proteins selected from Table 1, as described in the Example. The process of selecting the random combinations of each number of proteins (two proteins, three proteins, etc.) was performed for 1000 iterations.
  • AUC area-under-the-curve
  • ROC receiver operating characteristic
  • FIG.2 shows an ROC curve generated by application of a classifier, which depicts the high diagnostic utility of detecting ovarian cancer in a subject using the panel of 22 proteins listed in Table 2, as described in the Example.
  • FIG.3 shows an ROC curve generated by application of a classifier, which depicts the high diagnostic utility of detecting ovarian cancer in a subject using the panel of 42 proteins listed in Table 3, as described in the Example.
  • FIG.4 shows ROC curves generated by application of a classifier, which depict the high diagnostic utiltiy of detecting ovarian cancer in a subject using each of the 15 proteins listed in Table 4, both individualy (solid lines) and in combination (starred line), as described in the Example.
  • Units, prefixes, and symbols are denoted in their Système International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range, and any individual value provided herein can serve as an endpoint for a range that includes other individual values provided herein. For example, a set of values such as 1, 2, 3, 8, 9, and 10 is also a disclosure of a range of numbers from 1-10.
  • an “effective amount” can be determined empirically and in a routine manner, in relation to the stated purpose, route of administration, and dosage form.
  • subject or “individual” or “patient” means any subject, preferably a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include humans, domestic animals, farm animals, sports animals, and zoo animals including, e.g., humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, and so on.
  • an early-stage cancer in the context of cancer (e.g., “early-stage cancer” or cancer that “is early-stage”) refers generally to a level of advancement of the cancer prior to the cancer spreading to lymph nodes or tissues that are distant from the tissue of origin.
  • an early-stage cancer can refer to a cancer that is a Stage 0, Stage I, or Stage II cancer, based on the stage classification known in the art that grades cancer from Stage 0 (e.g., carcinoma in situ, where the cancer is still only in the layer of cells where it started and has not advanced farther), through Stages I-III (e.g., cancer is present—the higher Attorney Docket No.
  • this stage classification incorporates the TNM System, which evaluates the cancer based on the size and extent of the main tumor (“T”), the number of nearby lymph nodes that have cancer (“N”), and the extent to which the cancer has metastasized (“M”).
  • T main tumor
  • N the number of nearby lymph nodes that have cancer
  • M the extent to which the cancer has metastasized
  • symptomatic means to exhibit one or more signs or features that are regarded as indicative, or are known to be associated with, a disease or condition.
  • a subject may be considered as “symptomatic” of cancer based on symptoms that are known in the art to be associated with cancer in general or for specific types of cancer.
  • Examples include, but are not limited to, fatigue; lump or area of thickening that can be felt under the skin; weight changes, including unintended loss or gain; skin changes, such as yellowing, darkening, or redness of the skin, sores that will not heal, or changes to existing moles; changes in bowel or bladder habits; persistent cough or trouble breathing; difficulty swallowing; hoarseness; persistent indigestion or discomfort after eating; persistent, unexplained muscle or joint pain; persistent, unexplained fevers or night sweats; and unexplained bleeding or bruising.
  • Symptoms that can occur with ovarian cancer in particular include, but are not limited to, bloating, pelvic or abdominal pain; difficulty eating or feeling full quickly; urinary symptoms such as urgency or frequency; fatigue; upset stomach; back pain; pain during sex; constipation; change in menstruation such as heavier-than-normal or irregular bleeding; and abdominal swelling with weight loss.
  • a subject may be considered as “suspected of having a cancer” due to the presence of symptoms, i.e., the subject is symptomatic; genetic markers (e.g., mutations in BRCA1, BRCA2, RAS, BRAF, etc.); patient’s habits or medical history; patient’s family medical history; examination or tests known in the art for which the outcome is associated with cancer or risk of cancer, etc.
  • asymptomatic means to not exhibit any signs or features that are regarded as indicative, or are known to be associated with, a disease or condition.
  • Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder.
  • a subject is successfully Attorney Docket No. NVLNA.003.WO1 “treated” for a disease or disorder if the patient shows, e.g., total, partial, or transient alleviation or elimination of symptoms associated with the disease or disorder.
  • ROC or “ROC curve” is used to refer to a receiver operator characteristic curve.
  • a ROC curve can be a graphical representation of the performance of a classifier system.
  • a ROC can be generated by plotting the sensitivity against the specificity.
  • the sensitivity and specificity of a method for detecting the presence of a cancer or a specific type of cancer can be determined at various concentrations of proteins in a sample from the subject.
  • the AUC of a ROC curve is a metric that can provide a measure of diagnostic utility of a method, taking into account both the sensitivity and specificity of the method.
  • the AUC can range from 0.5 to 1.0, where a value closer to 0.5 can indicate that the method has limited diagnostic utility (e.g., lower sensitivity and/or specificity) and a value closer to 1.0 indicates the method has greater diagnostic utility (e.g., higher sensitivity and/or specificity).
  • the term “third party” means a person or group different from the two persons or groups primarily involved. For example, in a multi-step method involving a subject, a third party can be a person/group other than the subject and the person/group primarily responsible for the performance of the steps. In such an example, a third party may perform one of the steps in the method.
  • a third party may be a person/group other than the subject and the person/group administering the treatment.
  • cancer recurrence refers to a return of cancer after a period of remission. The cancer can reappear in the same, or close to, the place that it was previously found (local recurrence); in the lymph nodes and tissue located in the vicinity of the original cancer (regional recurrence); or in areas farther away from the original cancer (distant recurrence).
  • the present invention involves the use of proteins in the detection of evaluation of ovarian cancer in subjects (also referred to herein as “ovarian cancer detection Attorney Docket No. NVLNA.003.WO1 proteins”). Such use can be applied in methods of evaluating a subject for ovarian cancer, methods of treating subjects for ovarian cancer, among others.
  • the proteins can be used to detect or evaluate ovarian cancer based on a biological sample from the subject.
  • the biological sample may be any biological sample capable of being obtained from the subject, and encompass fluids, solids, tissues, and gases.
  • the sample may be a blood product, such as plasma, serum and the like.
  • the sample may be a urine sample, saliva sample, CSF sample, sweat sample, or tear sample.
  • the biological sample is advantageously a urine sample. Compared to blood or plasma samples, there is no homeostasis mechanism in urine that can regulate the presence of proteins in the course of maintaining relatively constant physical/chemical properties within the body (Jing, 2018). It is possible that potential biomarkers may be cleared from plasma or blood by the inherent homeostasis mechanism in order to avoid possible damage or interference to the body (id.).
  • An aspect of the present invention relates to a method of evaluating a subject for a cancer that is associated with the ovary; or a method of evaluating a subject for ovarian cancer.
  • the method comprises determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1.
  • the sample is already separated/obtained/collected from the subject at the time of the evaluation. In some embodiments, the sample is separated from the subject at home and/or by the subject prior to the evaluation. [0058] In embodiments of the invention, the method identifies whether the subject has ovarian cancer. The method may further comprise applying a classifier to the concentration of the one or more ovarian cancer detection proteins. The classifier identifies whether the concentration of the one or more ovarian cancer detection proteins is indicative that the subject has ovarian cancer. Attorney Docket No. NVLNA.003.WO1 [0059] In embodiments of the invention, the methods of evaluating a subject further comprise administering a treatment.
  • an aspect of the present invention relates to a method of treating ovarian cancer in a subject, comprising (a) acquiring results from methods of evaluating a subject for ovarian cancer as described herein, and (b) administering a treatment to the subject.
  • the results from methods of evaluating a subject for ovarian cancer are provided by a third party.
  • the treatment is responsive to the results, e.g., responsive to having ovarian cancer.
  • Another aspect of the present invention relates to a method of treating ovarian cancer in a subject, in which the method comprises (a) acquiring results from an evaluation of the subject that determined the subject has ovarian cancer; (b) administering a treatment to the subject, e.g., a treatment for ovarian cancer, in which the evaluation comprises: (I) determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1, and (II) applying a classifier to the concentration of the one or more proteins to identify whether the subject has ovarian cancer.
  • the results in (a) are acquired from a third party.
  • An aspect of the present invention relates to a method of detecting ovarian cancer in a subject, the method comprising determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1, and applying a classifier to the concentration of the one or more proteins that identifies whether the concentration of the one or more proteins is indicative that ovarian cancer is detected.
  • the method of detecting ovarian cancer in a subject further comprises administering a treatment. In some embodiments, the treatment is administered when ovarian cancer is detected.
  • an aspect of the present invention relates to a method of treating ovarian cancer in a subject, comprising (a) acquiring results from a method of detecting ovarian cancer in a subject as described herein, and (b) administering a treatment to the subject.
  • the results from the method of detecting ovarian cancer in a subject are provided by a third party.
  • the treatment is responsive to the results, e.g., responsive to ovarian cancer being detected.
  • An aspect of the invention relates to a method of treating ovarian cancer in a subject in whom ovarian cancer was detected, the method comprising administering a treatment for the ovarian cancer; in which the ovarian cancer had been detected in the subject by a method comprising determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1, and applying a classifier to the concentration of the one or more proteins to identify whether the subject has ovarian cancer.
  • the method of detecting the ovarian cancer was performed by a third party.
  • Yet another aspect of the present invention relates to a method of treating ovarian cancer in a subject, in which the method comprises (a) determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; (b) applying a classifier to the concentration of the one or more proteins to identify that the subject has ovarian cancer; and (c) administering a treatment to the subject, e.g., a treatment for ovarian cancer.
  • Another aspect of the present invention relates to a method of treating cancer in a patient who has been or was determined to have ovarian cancer, comprising administering a treatment for ovarian cancer to the patient, in which the patient was determined to have ovarian cancer by a method comprising (a) determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1, and (b) applying a classifier to the concentration of the one or more proteins.
  • the classifier identifies whether the concentration of the one or more proteins is indicative that the subject has ovarian cancer.
  • the subject is asymptomatic for ovarian cancer.
  • an aspect of the present invention relates to a method of evaluating a treatment for ovarian cancer in a subject.
  • the method comprises (a) administering a treatment for ovarian cancer, and (b) determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1.
  • the sample is already separated/obtained from the subject at the time of performing (b).
  • administration of the treatment in (a) may be performed by a third party.
  • determining the concentration of the one or more proteins in (b) may be performed by a third party.
  • the one or more proteins identifies whether the subject has ovarian cancer after treatment.
  • the method may further comprise applying a classifier to the concentration of the one or more proteins that identifies whether the concentration of the one or more proteins is indicative of the subject having ovarian cancer.
  • the treatment may be any known treatment for cancer as known in the art and as described herein.
  • the administration of the treatment in (a) may comprise a single administration or occurrence of a therapy, or may comprise multiple administrations or occurrences of a therapy.
  • the determination in a biological sample from the subject a concentration of one or more proteins in (b) may be performed more than once. The determination may overlap with the administration of the treatment in (a) or may occur after the administration of the treatment in (a).
  • the determination may occur immediately after the administration of the treatment or a period of time after the administration of the treatment.
  • the period of time may be one day or more, or one week or more, or one month or more, or one year or more; including one day, or two days, or three days, or four days, or five days, or six days, or about one week, or about two weeks, or about three weeks, or about four weeks, or about five weeks, or about six weeks, or about seven weeks, or about eight weeks, or about nine weeks, or about ten weeks, or about 11 weeks, or about 12 weeks, or about one month, or about two months, or about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months, or about nine months, or about ten months, or about 11 months, or about 12 months, or about one year, or about two years, or about three years, or about four years, or about five years, or about six years, or about seven years, or about eight years, or about nine years, or about ten months, or about 11 months, or about 12 months, or about one year, or about two years, or about three years, or about four
  • the presence of ovarian cancer after treatment may be indicative that the treatment was not effective.
  • another aspect of the invention is a method of evaluating the efficacy of an ovarian cancer treatment, comprising (a) administering a treatment for ovarian cancer, and (b) determining in a biological sample from the subject a concentration of one or more proteins, as described herein.
  • Yet another aspect is a method of treatment, comprising (a) administering a treatment for ovarian cancer, and (b) determining in a biological sample from the subject a concentration of one or more proteins, as described herein, to evaluate whether the treatment was effective.
  • the presence of ovarian cancer after treatment may be indicative that the treatment requires adjustment.
  • another aspect of the invention is a method of adjusting a treatment for ovarian cancer, comprising (a) administering a treatment for ovarian cancer, and (b) determining in a biological sample from the subject a concentration of one or more proteins, as described herein, to evaluate whether the treatment requires adjustment; such method may further comprise administering a second treatment.
  • the second treatment may be different from the original treatment, for example, a different therapy or different dosage of the same therapy.
  • the presence of ovarian cancer after treatment may be indicative of cancer recurrence.
  • another aspect of the invention is a method of monitoring for ovarian cancer recurrence, comprising (a) administering a treatment for ovarian cancer, and (b) determining in a biological sample from the subject a concentration of one or more proteins, as described herein.
  • a method of treatment comprising (a) administering a treatment for ovarian cancer, and (b) determining in a biological sample from the subject a concentration of one or more proteins, as described herein, to evaluate cancer recurrence.
  • the method may further comprise administering a second treatment when it is determined that the ovarian cancer is recurring.
  • the second treatment may be different from the original treatment, for example, a different therapy or different dosage of the same therapy.
  • Attorney Docket No. NVLNA.003.WO1 An aspect of the present invention relates to a method of measuring amounts of proteins in a subject, the method comprising determining individual amounts of one or more proteins selected from Table 1.
  • the individual amounts of the one or more proteins is determined in a biological sample from the subject.
  • the biological sample is a plasma sample, serum sample, saliva sample, CSF sample, sweat sample, urine sample, or tear sample.
  • the biological sample is a urine sample.
  • the methods may further comprise obtaining or collecting a biological sample from the subject before determining the concentration of one or more proteins in the biological sample.
  • the collection of the biological sample may be performed in a home (e.g., the home of the subject) or at a medical facility (e.g., doctor’s office, hospital, urgent care center, etc.).
  • the determination of the concentration of one or more proteins in the biological sample may be performed in a home (e.g., the home of the subject) or at a medical facility (e.g., doctor’s office, hospital, urgent care center, etc.).
  • the one or more proteins may be selected from Table 2.
  • the one or more proteins may be each protein of Table 2. [0083] In some embodiments of the invention, the one or more proteins may be selected from Table 3. In some embodiments of the invention, the one or more proteins may be each protein of Table 3. [0084] In some embodiments of the invention, the one or more proteins may be selected from Table 4. In some embodiments of the invention, the one or more proteins may be each protein of Table 4.
  • the methods may comprise determining the concentration of two or more, or three or more, or four or more, or five or more, or six or more, or seven or more, or eight or more, or nine or more, or ten or more, or about 15 or more, or about 20 or more, or about 25 or more, or about 30 or more, or about 35 or more, or about 40 proteins or more, or about 40 or more, or about 45 proteins or more, or about 50 proteins or more, or about 55 proteins or more, or about 60 proteins or more, proteins; including any number of proteins chosen Attorney Docket No.
  • NVLNA.003.WO1 to 40 proteins or about 30 to 35 proteins, or about 35 to 65 proteins, or about 35 to 60 proteins, or about 35 to 55 proteins, or about 35 to 50 proteins, or about 35 to 45 proteins, or about 35 to 40 proteins, or about 40 to 65 proteins, or about 40 to 60 proteins, or about 40 to 55 proteins, or about 40 to 50 proteins, or about 40 to 45 proteins, or about 45 to 65 proteins, or about 45 to 60 proteins, or about 45 to 55 proteins, or about 45 to 50 proteins, or about 50 to 65 proteins, or about 50 to 60 proteins, or about 50 to 55 proteins, or about 55 to 65 proteins, or about 60 to 65 proteins. [0086] In some embodiments, the methods may comprise determining the concentration of each protein of Table 1.
  • the methods may comprise determining the concentration of each protein of Table 2. In certain embodiments, the methods may comprise determining the concentration of each protein of Table 3. In certain embodiments, the methods may comprise determining the concentration of each protein of Table 4. [0087] In some embodiments, the number of proteins for which the concentration is determined may be sufficient to achieve an AUC of a ROC curve of at least about 0.6. In certain embodiments, the number of proteins for which the concentration is determined may be sufficient to achieve an AUC of a ROC curve of at least about 0.7, or at least about 0.8, or at least about 0.9. [0088] In embodiments of the invention, the ovarian cancer is early-stage. In some embodiments, the ovarian cancer is stage I.
  • the ovarian cancer is stage II. [0089] In some embodiments, the ovarian cancer is stage III. In some embodiments, the ovarian cancer is stage IV. In some embodiments, the ovarian cancer is stage V. [0090]
  • the treatment administered to the subjects according to the methods described herein may be treatments known in the art. Examples of such treatments include, but are not limited to, surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapy, and any combination thereof.
  • Examples of surgery may include, but are not limited, to bilateral salpingo-oophorectomy (removal of the ovaries and fallopian tubes); hysterectomy, such as a simple hysterectomy (removal of the uterus and cervix) or radical hysterectomy (removal of the entire uterus, tissues next to the uterus, and the upper part of the vagina); omentectomy (removal of omentum); lymph node dissection (removal of lymph nodes, such as those in the Attorney Docket No. NVLNA.003.WO1 pelvis or around the aorta); and any combination thereof.
  • hysterectomy such as a simple hysterectomy (removal of the uterus and cervix) or radical hysterectomy (removal of the entire uterus, tissues next to the uterus, and the upper part of the vagina); omentectomy (removal of omentum); lymph node dissection (remov
  • Examples of radiation therapy include, but are not limited to, brachytherapy, external beam radiation therapy, and a combination thereof.
  • chemotherapy include, but are not limited to, paclitaxel, albumin-bound paclitaxel, altretamine, capecitabine, cisplatin, cyclophosphamide, dactinomycin, etoposide, gemcitabine, ifosfamide, irinotecan, doxorubicin, melphalan, pemetrexed, topotecan, vinblastine, vinorelbine, and any combination thereof.
  • hormone therapy examples include, but are not limited to, luteinizing-hormone-releasing hormone agonists such as goserelin and/or leuprolide; tamoxifen; aromatase inhibitors such as letrozole, anastrozole, and/or exemestane; and any combination thereof.
  • targeted therapy examples include, but are not limited to, angiogenesis inhibitors such as bevacizumab; poly(ADP)-ribose polymerase (PARP) inhibitors such as olaparib, rucaparib, and/or niraparib; drugs that target folate receptor-alpha such as mirvetuximab soravtansine; drugs that target cells with NTRK gene changes such as larotrectinib and/or entrectinib; and a combination thereof.
  • angiogenesis inhibitors such as bevacizumab
  • PARP poly(ADP)-ribose polymerase
  • olaparib rucaparib
  • niraparib niraparib
  • drugs that target folate receptor-alpha such as mirvetuximab soravtansine
  • drugs that target cells with NTRK gene changes such as larotrectinib and/or entrectinib
  • a combination thereof include, but are not limited to, angiogenesis inhibitor
  • Survival can be overall survival, i.e., length of time a patient lives, or progression-free survival, i.e., length of time a patient is treated without progression of the disease. Survival can be measured from the date of diagnosis or from the date that treatment commences. Overall survival, median overall survival, progression-free survival, and median progression-free survival can be determined by methods known in the art and/or by those described herein. [0092] In certain embodiments a patient with ovarian cancer subjected to a method of the invention is successfully treated if the patient has an improved response to the anti-cancer therapy compared with a patient having ovarian cancer who has not been subjected to a method of the invention.
  • treatment of ovarian cancer would be successful in a subject treated by the methods of the invention if the subject has an improved response compared to the median response of patients who have not been treated by the methods of the invention.
  • Response to anti-cancer treatment can be measured by known methods appropriate to the cancer type, for instance, using Response Evaluation Criteria in Solid Tumors (RECIST). Patients evaluated using RECIST can have a complete response (CR), a partial response (PR), stable disease (SD), or progressive disease (PD).
  • RECIST Response Evaluation Criteria in Solid Tumors
  • Patients evaluated using RECIST can have a complete response (CR), a partial response (PR), stable disease (SD), or progressive disease (PD).
  • An improved Attorney Docket No. NVLNA.003.WO1 response can also be assessed by other criteria, for example, duration of response, reduction in tumor volume, minimum residual disease (MRD), and the like.
  • the concentration of proteins in the sample may be measured using protein quantitation techniques known in the art. Such techniques include, but are not limited to, enzyme-linked immunosorbent assays, chemiluminescence immunoassays, immunohistochemistry, liquid-bead immunoassays, mass spectrometry, aptamer-based assays, reverse phase protein arrays, proximity extension assay (PEA), and a combination thereof.
  • concentration of the two or more proteins are used and combined with mathematical, statistical, and machine-learning methods to create secondary features.
  • One or more proteins with and without secondary features and baseline features including age, sex, race and ethnicity, past medical history, family history, patient’s lab values, comorbidities, and concomitant medications, are used in one or more predictive models to calculate a score.
  • Supervised learning concepts may include AODE; Artificial neural network, such as Backpropagation, Auto encoders, Hopfield networks, Boltzmann machines, Restricted Boltzmann Machines, and Spiking neural networks; Bayesian statistics, such as Bayesian network and Bayesian knowledge base; Case-based reasoning; Gaussian process regression; Gene expression programming; Group method of data handling (GMDH); Inductive logic programming; Instance-based learning; Lazy learning; Learning Automata; Learning Vector Quantization; Logistic Model Tree; Minimum message length (decision trees, decision graphs, etc.), such as Nearest Neighbor Algorithm and Analogical modeling; Probably approximately correct learning (PAC ) learning; Ripple down rules, a knowledge acquisition methodology; Symbolic machine learning algorithms; Support vector machines; Random Forests; Ensembles of classifiers, such as Bootstrap aggregating (bagging) and Boosting (meta -
  • Unsupervised learning concepts may include; Expectation –maximization algorithm; Vector Quantization; Generative topographic map; Information bottleneck method; Artificial neural network, such as Self - organizing map; Association rule learning, such as Apriori algorithm, Eclat algorithm, and FP growth algorithm; Hierarchical clusterings such as Single linkage clustering and Conceptual clustering; Cluster analysis, such as K -means algorithm, Fuzzy clustering, DBSCAN, and OPTICS algorithm; and Outlier Detection, such as Local Outlier Factor.
  • Semi-supervised learning concepts may include; Generative models; Low –density separation; Graph-based methods, and Co -training.
  • Reinforcement learning concepts may include Temporal difference learning; Q -learning, Learning Automata, and SARSA.
  • Deep learning concepts may include Deep belief networks; Deep Boltzmann machines; Deep Convolutional neural networks; Deep Recurrent neural networks; and Hierarchical temporal memory.
  • concentrations obtained from detection proteins one or more features are fed into one or more computation models.
  • the classifiers are used to calculate a score for the patient.
  • the scores of different classifiers are combined to identify the patient as having the specific cancer or not.
  • the computational model may use one or more proteins or secondary features with and without baseline features that could generate a (ROC curve greater than or equal to 0.6. This step determines if the sample indicates the presence of the cancer.
  • Protein concentrations and/or secondary features are fed into one or more predictive models. The features could be similar or different from what was used in determining cancer status.
  • the classifiers are used to calculate a score for the patient for ovarian cancer.
  • the predictive models use the proteins or derived secondary features that could generate a ROC curve greater than or equal to 0.6.
  • machine learning algorithms are used to construct models that accurately assign class labels to examples based on the input features that describe the example.
  • kits for use in detecting one or more ovarian cancer detection proteins i.e., one or more proteins of Table 1, or one or more proteins of Table 2, or one or more proteins of Table 3, or one or more proteins of Table 4, or each protein of Table 4, which can be used to perform the methods described herein.
  • the kit may comprise one or more components that can be used to perform assays such as enzyme-linked immunosorbent assays, chemiluminescence immunoassays, immunohistochemistry, liquid-bead immunoassays, mass spectrometry, aptamer-based assays, reverse phase protein arrays, PEA, or a combination thereof.
  • kits comprises antibodies or antigen binding fragments thereof that bind two or more, or three or more, or four or more, or five or more, or six or more, or seven or more, or eight or more, or nine or more, or ten or more, or about 15 or more, or about 20 or more, or about 25 or more, or about 30 or more, or about 35 or more, or about 40 proteins or more, or about 40 or more, or about 45 proteins or more, or about 50 proteins or more, or about 55 proteins or more, or about 60 proteins or more proteins; including any number of proteins chosen from two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,
  • the kit may also comprise one or more enzymes, substrates, labels, or other components useful for performing the assays.
  • the kit further comprises one or more of the following: one or more containers for collecting or holding the sample (e.g., urine sample), controls, directions for performing the methods, any necessary software for analysis and presentation of results.
  • Attorney Docket No. NVLNA.003.WO1 [00104] One skilled in the art will readily recognize that the disclosed one or more components can be readily incorporated into any of the established kit formats that are well known in the art.
  • EXAMPLE Analyses were performed to identify the ovarian cancer detection proteins of the present invention.
  • each of the two antibodies was conjugated to one of two different DNA oligonucleotides, and the reagents were incubated with the samples in solution.
  • the proximity reactions underwent a dilution step.
  • Oligonucleotides on pairs of antibodies that remain in proximity by virtue of having bound the same protein molecule then underwent DNA ligation (proximity ligation assay) or DNA polymerization (proximity extension assay).
  • the effect of the ligation or polymerization reactions was to create amplifiable reporter DNA strands for sensitive readout via, for example, real-time PCR or next-generation sequencing, and the assays could be performed in high multiplex.
  • Deep learning concepts may include deep belief networks; deep Boltzmann machines; deep convolutional neural networks; deep recurrent neural networks; and hierarchical temporal memory.
  • Ovarian Cancer Detection Proteins [00112] One or more features were fed into one or more computation models. The classifiers were used to calculate a score for the patient. The scores of different classifiers were combined to identify the patient as having ovarian cancer or not. The computational model only selected protein or protein combinations that could generate a receiver operating characteristic (ROC) curve of greater than or equal to 0.6. The resulting ovarian cancer detection proteins are shown in Table 1. FIG.1 shows that the accuracy is over 0.7 when any two proteins through any 20 proteins are randomly selected.
  • ROC receiver operating characteristic
  • the model also identified particular substes of the proteins of Table 1 from which one or more proteins can be selected from to detect ovarian cancer. Such subsets are presented in Table 2, Table 3, and Table 4. In addition, it was determined that panels of the proteins of Table 2, Table 3, and Table 4 each exhibits high diagnostic utiltiy: the ROC curve generated from the panel of all of the proteins listed in Table 2 has an AUC of about 0.894 (see FIG.2), the ROC curve generated from the panel of all of the proteins listed in Table 3 has an AUC of about 0.942 (see FIG.3), and the ROC curve generated from the panel of all of the proteins listed in Table 4 has an AUC of about 0.974 (see FIG.4).
  • Embodiment 1 A method of evaluating a subject for ovarian cancer, the method comprising: determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; thereby evaluating the subject for cancer.
  • Embodiment 2. The method of Embodiment 1, further comprising applying a classifier to the concentration of the one or more proteins that identifies whether the concentration of the one or more proteins is indicative of the subject having ovarian cancer.
  • Embodiment 3 The method of Embodiment 1 or 2, further comprising administering a treatment to the subject.
  • a method of treating ovarian cancer in a subject comprising (a) acquiring results from the method of Embodiments 1 or 2; and (b) administering a treatment to the subject.
  • Embodiment 5. The method of Embodiment 4, wherein the treatment is responsive to the results acquired in (a).
  • Embodiment 7 A method of treating ovarian cancer in a subject, the method comprising: Attorney Docket No.
  • NVLNA.003.WO1 (a) acquiring results from an evaluation of the subject that determined the subject has ovarian cancer; (b) administering a treatment to the subject, wherein the evaluation comprises: (i) determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; and (ii) applying a classifier to the concentration of the one or more proteins to identify whether the subject has ovarian cancer.
  • Embodiment 8 The method of any one of Embodiments 4-8, wherein the results in (a) are acquired from a third party.
  • a method of detecting ovarian cancer in a subject comprising: determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; and applying a classifier to the concentration of the one or more proteins that identifies whether the concentration of the one or more proteins is indicative that ovarian cancer is detected.
  • Embodiment 10. The method of Embodiment 9, further comprising administering a treatment to the subject.
  • Embodiment 11. A method of treating ovarian cancer in a subject, comprising (a) acquiring results from the method of Embodiment 9; and (b) administering a treatment to the subject.
  • Embodiment 12 The method of Embodiment 11, wherein the treatment is responsive to the results acquired in (a).
  • Embodiment 13 A method of treating ovarian cancer in a subject, the method comprising determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; applying a classifier to the concentration of the one or more proteins that identifies whether the concentration of the one or more proteins is indicative that ovarian cancer is detected; and administering a treatment to the subject when ovarian cancer is detected.
  • Embodiment 14 A method of treating ovarian cancer in a subject, the method comprising determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; applying a classifier to the concentration of the one or more proteins that identifies whether the concentration of the one or more proteins is indicative that ovarian cancer is detected; and administering a treatment to the subject when ovarian cancer is detected.
  • a method of treating ovarian cancer in a subject in whom ovarian cancer was detected comprising administering a treatment for ovarian cancer to the subject, wherein ovarian cancer was detected in the subject by a method comprising: determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; and applying a classifier to the concentration of the one or more proteins that identifies whether the concentration of the one or more proteins is indicative that ovarian cancer is detected.
  • Embodiment 15 The method of Embodiment 14, wherein the method of detecting ovarian cancer was performed by a third party.
  • Embodiment 16 The method of any one of Embodiments 1-15, wherein the ovarian cancer is early-stage.
  • Embodiment 20 A method of evaluating a treatment for ovarian cancer in a subject, the method comprising: administering a treatment for ovarian cancer, and determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; thereby evaluating the treatment.
  • Embodiment 21 A method of evaluating a treatment for ovarian cancer in a subject, the method comprising: administering a treatment for ovarian cancer, and determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; thereby evaluating the treatment.
  • a method of evaluating the efficacy of a treatment for ovarian cancer in a subject comprising (a) administering a treatment for ovarian cancer to the subject, and (b) determining in a biological sample from the subject a concentration of one or more proteins selected from Table 1; thereby evaluating the efficacy of the treatment.
  • Embodiment 22 A method of treating ovarian cancer in a subject, the method comprising (a) administering a treatment for ovarian cancer to the subject, and (b) determining in a biological sample from the subject a concentration of one or more proteins to evaluate the efficacy of the treatment, wherein the one or more proteins are selected from Table 1.
  • Embodiment 23 A method of evaluating the efficacy of a treatment for ovarian cancer in a subject, the method comprising (a) administering a treatment for ovarian cancer to the subject, and (b) determining in a biological sample from the subject a concentration of one or more proteins to evaluate the efficacy of the treatment, wherein the one or more
  • a method of adjusting a treatment for ovarian cancer in a subject comprising (a) administering a treatment for ovarian cancer to the subject, (b) determining in a biological sample from the subject a concentration of one or more proteins, wherein the one or more proteins are selected Table 1, and (c) administering an adjusted treatment to the subject when it is determined that the adjusted treatment is necessary.
  • Embodiment 24 A method of treating ovarian cancer in a subject, the method comprising (a) administering a treatment for ovarian cancer to the subject, and Attorney Docket No. NVLNA.003.WO1 (b) determining in a biological sample from the subject a concentration of one or more proteins to evaluate whether the treatment requires adjustment, wherein the one or more proteins are selected from Table 1.
  • Embodiment 25 The method of Embodiment 24, further comprising administering an adjusted treatment when it is determined that the adjusted treatment is necessary.
  • Embodiment 26 A method of monitoring for ovarian cancer recurrence in a subject, comprising (a) administering a treatment for ovarian cancer to the subject, and (b) determining in a biological sample from the subject a concentration of one or more proteins to evaluate whether the ovarian cancer is recurring, wherein the one or more proteins are selected from Table 1.
  • Embodiment 27 A method of monitoring for ovarian cancer recurrence in a subject, comprising (a) administering a treatment for ovarian cancer to the subject, and (b) determining in a biological sample from the subject a concentration of one or more proteins to evaluate whether the ovarian cancer is recurring, wherein the one or more proteins are selected from Table 1.
  • a method of treating ovarian cancer in a subject comprising (a) administering a treatment for ovarian cancer to the subject, and (b) determining in a biological sample from the subject a concentration of one or more proteins to evaluate whether cancer is recurring, wherein the one or more proteins are selected from Table 1.
  • Embodiment 28 The method of Embodiment 26 or 27, further comprising administering a second treatment when it is determined that the cancer is recurring.
  • Embodiment 29 The method of any one of Embodiments 20-28, further comprising applying a classifier to the concentration of the one or more proteins that identifies whether the concentration of the one or more proteins is indicative of the subject having ovarian cancer.
  • Embodiment 30 Embodiment 30.
  • Embodiments 1-29 wherein the biological sample is selected from a plasma sample, serum sample, saliva sample, CSF sample, sweat sample, urine sample, or tear sample.
  • Attorney Docket No. NVLNA.003.WO1 Embodiment 31 The method of Embodiment 30, wherein the biological sample is a urine sample.
  • Embodiment 32 The method of any one of Embodiments 1-31, further comprising collecting the biological sample from the subject.
  • Embodiment 33 The method of Embodiment 32, wherein the collection of the biological sample is performed in the home of the subject.
  • Embodiment 34 The method of Embodiment 33, wherein the collection of the biological sample is performed in a medical facility.
  • Embodiment 37 The method of any one of Embodiments 1-36, wherein the number of proteins for which the concentration is determined is sufficient to achieve an area-under-the- curve (AUC) of a ROC curve of at least about 0.6.
  • Embodiment 38 The method of Embodiment 37, wherein the number of proteins for which the concentration is determined is sufficient to achieve an AUC of a ROC curve of at least about 0.7.
  • Embodiment 38 wherein the number of proteins for which the concentration is determined is sufficient to achieve an AUC of a ROC curve of at least about 0.8.
  • Attorney Docket No. NVLNA.003.WO1 Embodiment 40 The method of any one of Embodiments 1-39, wherein the concentration of the two or more proteins is determined by one or more assays.
  • Embodiment 41 The method of any one of Embodiments 20-40, wherein the administration of the treatment in (a) is performed by a third party.
  • Embodiment 42 The method of any one of Embodiments 20-40, wherein the determination in a urine sample from the subject a concentration of one or more proteins in (b) is performed by a third party.
  • Embodiment 43 The method of any one of Embodiments 20-40, wherein the determination in a urine sample from the subject a concentration of one or more proteins in (b) is performed by a third party.
  • a method of measuring amounts of proteins in a subject comprising determining individual amounts of one or more proteins selected from Table 1.
  • Embodiment 44 The method of any one of Embodiments 1-43, wherein the one or more proteins are selected from Table 2.
  • Embodiment 45 The method of any one of Embodiments 1-43, wherein the one or more proteins are selected from Table 3.
  • Embodiment 46 The method of any one of Embodiments 1-43, wherein the one or more proteins are selected from Table 4.
  • Embodiment 47 The method of any one of Embodiments 1-46, wherein two or more proteins are selected.
  • Embodiment 48 The method of any one of Embodiments 1-46, wherein three or more proteins are selected.
  • Embodiment 49 The method of any one of Embodiments 1-46, wherein three or more proteins are selected.
  • Embodiment 50 The method of any one of Embodiments 1-46, wherein five or more proteins are selected.
  • Embodiment 50 The method of any one of Embodiments 1-46, wherein ten or more proteins are selected.
  • Attorney Docket No. NVLNA.003.WO1 Embodiment 51 The method of any one of Embodiments 1-45, wherein 20 or more proteins are selected.
  • Embodiment 52 The method of any one of Embodiments 1-43 or 45, wherein 30 or more proteins are selected.
  • Embodiment 53 The method of any one of Embodiments 1-43 or 45, wherein 40 or more proteins are selected.
  • Embodiment 54 The method of any one of Embodiments 1-43, wherein 50 or more proteins are selected.
  • Embodiment 55 The method of any one of Embodiments 1-43, wherein 50 or more proteins are selected.
  • Embodiment 56 The method of any one of Embodiments 1-46, wherein all proteins are selected.
  • Embodiment 57. The method of any one of Embodiments 1-43, wherein no more than about 60 proteins are selected.
  • Embodiment 58. The method of any one of Embodiments 1-43, wherein no more than about 50 proteins are selected.
  • Embodiment 59. The method of any one of Embodiments 1-43 or 45, wherein no more than about 40 proteins are selected.
  • Embodiment 60 The method of any one of Embodiments 1-43 or 45, wherein no more than about 30 proteins are selected.
  • Embodiments 1-45 The method of any one of Embodiments 1-45, wherein no more than about 20 proteins are selected.
  • Attorney Docket No. NVLNA.003.WO1 Embodiment 62 The method of any one of Embodiments 1-46, wherein no more than about ten proteins are selected.
  • Embodiment 63 The method of any one of Embodiments 1-46, wherein no more than about five proteins are selected.

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Abstract

L'invention concerne des procédés d'évaluation d'un sujet pour le cancer de l'ovaire ou de détection du cancer de l'ovaire chez un sujet, les procédés comprenant la détermination, dans un échantillon biologique provenant du sujet, d'une concentration d'une ou de plusieurs protéines choisies dans le tableau 1. Les procédés peuvent en outre comprendre l'application d'un classificateur à la concentration de la ou des protéines qui identifie si la concentration de la ou des protéines indique que le sujet est atteint d'un cancer de l'ovaire. De plus, l'invention concerne des méthodes de traitement comprenant l'administration d'un traitement au sujet lorsque le sujet est évalué ou détecté comme ayant un cancer de l'ovaire.
PCT/US2024/019543 2023-03-12 2024-03-12 Protéines de détection du cancer de l'ovaire et leurs procédés d'utilisation Ceased WO2024192004A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140220580A1 (en) * 2011-06-16 2014-08-07 Kirk Brown Biomarker compositions and methods
US20140228233A1 (en) * 2011-06-07 2014-08-14 Traci Pawlowski Circulating biomarkers for cancer
US20180340945A1 (en) * 2017-05-24 2018-11-29 Nanosomix, Inc. Detection of biomarkers on vesicles for the diagnosis and prognosis of diseases and disorders
US20200377956A1 (en) * 2017-08-07 2020-12-03 The Johns Hopkins University Methods and materials for assessing and treating cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140228233A1 (en) * 2011-06-07 2014-08-14 Traci Pawlowski Circulating biomarkers for cancer
US20140220580A1 (en) * 2011-06-16 2014-08-07 Kirk Brown Biomarker compositions and methods
US20180340945A1 (en) * 2017-05-24 2018-11-29 Nanosomix, Inc. Detection of biomarkers on vesicles for the diagnosis and prognosis of diseases and disorders
US20200377956A1 (en) * 2017-08-07 2020-12-03 The Johns Hopkins University Methods and materials for assessing and treating cancer

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